Remarkable advances with hepatitis C Virus (HCV) infection therapy have been made over the past 5 years,. At the same time, the peak of morbidity for the HCV epidemic, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC) will not occur until 2030. In fact, HCC is one of the fastest growing cancer related causes of death in the US. Certainly, at some point successful therapy for HCV will reduce the incidence of HCC. Though when this will be realized is unclear, in part due to the fact that the chronic HCV- infected patient population is aging, and older age HCV-infected patients do not appear to derive the same reduction in morbidity after successful HCV therapy as do their younger counterparts. At present, our local VA station (Station 541, Cleveland) follows 3,428 HCV patients, and over the past 3 years has treated over 1,500 of these with IFN-free therapy. Still, we accrue 25-43 new HCC cases/year, running at a steady rate over the past 6 years. Better strategies to more precisely identify those at high risk for HCC, and treat early HCC are much needed to curb this morbidity/mortality. PD1 blockade is an emerging therapy, and while a role for T cells in mediating effects of PD1 blockade have been defined, a role for NK cell activity is less defined. At the same time NK cells are a dominant lymphocyte population within the liver, NK cells are known to contribute to control of HCV infection itself, and NK cells have anti-cancer effector function. We will follow our well characterized HCV infected patient population, taking an NK cell, pathway focused approach to evaluate the anti-tumor host immune response that precedes HCV associated HCC diagnosis, to help identify both predictive markers and new treatment strategies. We hypothesize that NK cells play an integral role in host defense against HCV associated HCC, that selective enhancement of NK cell immune function through modulation of the IFN response or PD1 signaling can be harnessed to improve host anti-HCC immunity with therapeutic potential. Defining NK cell immunity that precedes HCC diagnosis will inform when and how to best inform PD1 or NK targeted clinical trial design, and potentially provide biomarkers of disease risk or onset. We will investigate this hypothesis with the following aims: Aim 1: Determine the role of PD1 on NK cell expansion and anti-HCC activity. Aim 2: Determine the effect of selective targeting the Long Non-Coding RNA (lncRNA) NRIR (negative regulator of interferon response) in enhancing IFN-dependent anti-HCC activity. Aim 3: Define NK cell activation state, function, PD1 pathway engagement and IFN regulatory pathway engagement prior to diagnosis of HCC.